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Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.

Background The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well. Purpose The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss. Data Collection and Analysis Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www.ClinicalTrials.gov) database identified 61 clinical trials. Results Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss. Conclusion This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field. [ABSTRACT FROM AUTHOR]

Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials. [ABSTRACT FROM AUTHOR]

Acquired hearing loss, which can develop after noise insult or ototoxic drug treatment, is a significant clinical, social, and economic issue. A major advance in our understanding came with the discovery that intense metabolic activity in the inner ear drives the formation of free radicals (short-lived, unstable, highly reactive clusters of atoms) in multiple types of cells in the inner ear after both noise and drug insult. Animal studies have now shown that free radicals formed during and after metabolic stress importantly contribute to acquired hearing loss. These new mechanistic insights provided for the first time a rationalefor directly treating the inner ear to prevent hearing impairment. Consequently, use of free radical scavengers, or antioxidants, to prevent acquired hearing loss became a clinically relevant research goal. Many laboratories have now demonstrated that a variety of free radical scavengers reduce the potential for acquired hearing loss in animal subjects. Scientific data, supporting the use of these agents to preventenvironmentally acquired hearing loss, is reviewed. Translational investigations are now essential to confirm the potential utility of these agents in the human inner ear. This article reviews the pharmacological otoprotective agents in or approaching clinical trials to prevent noise-, aminoglycoside-, and cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]

Systemic and local changes in body temperature can have a profound effect on traumatic injuries including those to the inner ear. Therefore, we investigated the effects of acutely increasing or decreasing the temperature of the external ear canal on cisplatin-induced hearing loss. The external auditory canals of male guinea pigs were acutely irrigated with warm (44 °C), euthermic (37 °C), or cool (30 °C) water and subsequently injected with cisplatin (12 mg/kg, i.p.). Hearing was assessed by the auditory brainstem response and cochleograms were prepared to determine loss of hair cells. Ear canal irrigation with warm water potentiated cisplatin-induced hearing loss and outer hair cell loss whereas cool ear canal irrigation showed significant protection from cisplatin-induced hearing loss and outer hair cell loss. These results suggest that non-invasive cool water ear canal irrigation may be highly effective clinical procedure for protecting against cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]